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The Journal of Neuroscience, June 15, 2005, 25(24):5740-5749; doi:10.1523/JNEUROSCI.0913-05.2005

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Behavioral/Systems/Cognitive
Endogenous Activation of Metabotropic Glutamate Receptors Modulates GABAergic Transmission to Gonadotropin-Releasing Hormone Neurons and Alters Their Firing Rate: A Possible Local Feedback Circuit

Zhiguo Chu¹ and Suzanne M. Moenter^1,2

Departments of ¹Internal Medicine and ²Cell Biology, University of Virginia, Charlottesville, Virginia 22908

Gonadotropin-releasing hormone (GnRH) neurons are the primary central regulators of fertility, receiving input from GABAergic afferents via GABA_A receptors. We tested whether metabotropic glutamate receptors (mGluRs) regulate GABA transmission to GnRH neurons and GnRH neuronal firing pattern. Whole-cell recordings were performed under conditions isolating ionotropic GABA postsynaptic currents (PSCs) in brain slices. The broad-spectrum mGluR agonist 1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) decreased the frequency of GABA_A-mediated spontaneous PSCs in a reversible manner. Amplitude and kinetics were not altered, suggesting that afferent GABA neurons are the primary targets. TTX eliminated the effects of ACPD in most tested neurons. Group II [2-(2,3-dicarboxycyclopropyl) glycine] and III (L-AP-4) mGluR agonists mediated this response; a group I agonist (3,5-dihydroxyphenylglycine) was not effective. The broad-spectrum antagonist -methyl-4-carboxyphenylglycine (MCPG) and/or (RS)--cyclopropyl-4-phosphonophenylglycine (CPPG) (group III antagonist) enhanced spontaneous PSC frequency, particularly when initial frequency was low, suggesting that endogenous activation of mGluRs regulates GABA transmission to GnRH neurons. Extracellular recordings were used to evaluate GnRH neuron firing rate within the network. ACPD reduced firing rate, and MCPG plus CPPG had an opposite effect, indicating that mGluRs help control excitability of the GnRH network. GnRH neurons express vesicular glutamate transporters, suggesting they may corelease this transmitter. Simulation of firing activity in a GnRH neuron decreased PSC frequency in that cell, an effect blocked by antagonism of mGluRs but not GnRH receptors. These results demonstrate an inhibition of GABAergic inputs to GnRH neurons by mGluRs via a presynaptic mechanism. Through this mechanism, local glutamate milieu, possibly contributed by GnRH neurons themselves, plays an important role in modulating GnRH release and the central regulation of fertility.

Key words: GnRH; mGluR; GABA; presynaptic; IPSC; firing pattern

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Received Jan 10, 2005; revised April 29, 2005; accepted May 8, 2005.

This article has been cited by other articles:

				C. A. Christian and S. M. Moenter Vasoactive Intestinal Polypeptide Can Excite Gonadotropin-Releasing Hormone Neurons in a Manner Dependent on Estradiol and Gated by Time of Day Endocrinology, June 1, 2008; 149(6): 3130 - 3136. [Abstract] [Full Text] [PDF]

				J. Pielecka-Fortuna, Z. Chu, and S. M. Moenter Kisspeptin Acts Directly and Indirectly to Increase Gonadotropin-Releasing Hormone Neuron Activity and Its Effects Are Modulated by Estradiol Endocrinology, April 1, 2008; 149(4): 1979 - 1986. [Abstract] [Full Text] [PDF]

				C. A. Christian and S. M. Moenter Estradiol Induces Diurnal Shifts in GABA Transmission to Gonadotropin-Releasing Hormone Neurons to Provide a Neural Signal for Ovulation J. Neurosci., February 21, 2007; 27(8): 1913 - 1921. [Abstract] [Full Text] [PDF]

				Y. Lu Endogenous mGluR Activity Suppresses GABAergic Transmission in Avian Cochlear Nucleus Magnocellularis Neurons J Neurophysiol, February 1, 2007; 97(2): 1018 - 1029. [Abstract] [Full Text] [PDF]

				Z. Chu and S. M. Moenter Physiologic Regulation of a Tetrodotoxin-Sensitive Sodium Influx That Mediates a Slow Afterdepolarization Potential in Gonadotropin-Releasing Hormone Neurons: Possible Implications for the Central Regulation of Fertility. J. Neurosci., November 15, 2006; 26(46): 11961 - 11973. [Abstract] [Full Text] [PDF]

				J. Pielecka and S. M. Moenter Effect of Steroid Milieu on Gonadotropin-Releasing Hormone-1 Neuron Firing Pattern and Luteinizing Hormone Levels in Male Mice Biol Reprod, May 1, 2006; 74(5): 931 - 937. [Abstract] [Full Text] [PDF]

				J. Pielecka, S. D. Quaynor, and S. M. Moenter Androgens Increase Gonadotropin-Releasing Hormone Neuron Firing Activity in Females and Interfere with Progesterone Negative Feedback Endocrinology, March 1, 2006; 147(3): 1474 - 1479. [Abstract] [Full Text] [PDF]

				S. M. Moenter and R. A. DeFazio Endogenous {gamma}-Aminobutyric Acid Can Excite Gonadotropin-Releasing Hormone Neurons Endocrinology, December 1, 2005; 146(12): 5374 - 5379. [Abstract] [Full Text] [PDF]

				C. A. Christian, J. L. Mobley, and S. M. Moenter Diurnal and estradiol-dependent changes in gonadotropin-releasing hormone neuron firing activity PNAS, October 25, 2005; 102(43): 15682 - 15687. [Abstract] [Full Text] [PDF]

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